Ketone derivatives

ABSTRACT

The present invention provides ketones of the general formula (I): ##STR1## and physiologically acceptable salts and solvates thereof, wherein R 1  and R 2 , which may be the same or different, each represents a hydrogen atom or a C 1-6  alkyl group; Im represents an imidazolyl group of formula: ##STR2## wherein one of the groups represented by R 3 , R 4  and R 5  is a hydrogen atom or a C 1-6  alkyl, C 3-7  cycloalkyl, C 3-6  alkenyl, phenyl or phenylC 1-3  alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C 1-6  alkyl group; and 
     A is a group of the formula (a), (b), (c), (d), (e), (f) or (g) as set forth hereinafter, 
     and when A is the group (g), the group --COCR 1  R 2  CH 2  Im is attached at the 2- or 4- position of the indole moiety. 
     The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT 3  receptors and are useful, for example, in the treatment of psychotic disorders, anxiety and nausea and vomiting.

This application is a division of application Ser. No. 07/440,880, filedNov. 24, 1989, now allowed, which is a division of application Ser. No.07/180,960, filed Apr. 13, 1988, now U.S. Pat. No. 4,918,080.

This invention relates to ketone derivatives, to processes for theirpreparation, to pharmaceutical compositions containing them and to theirmedical use. In particular the invention relates to compounds which actupon 5-hydroxytryptamine (5-HT) receptors of the type located onterminals of primary afferent nerves.

Compounds having antagonist activity at `neuronal` 5-HT receptors of thetype located on primary efferent nerves have been described previously.

Thus for example published UK Patent Specification No. 2153821A andpublished European Patent Specifications Nos. 191562, 219193 and 210840disclose 3-imidazolylmethyltetrahydrocarbazolones which may berepresented by the general formula: ##STR3## wherein R¹ represents ahydrogen atom or a group selected from C₁₋₁₀ alkyl, C₃₋₆ alkenyl, C₃₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, phenyl orphenylC₁₋₃ alkyl, and in the case where Q represents a hydrogen atom, R¹may also represent --CO₂ R⁵, --COR⁵, --CONR⁵ R⁶ or --SO₂ R⁵ (wherein R⁵and R⁶, which may be the same or different, each represents a hydrogenatom, a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or a phenyl or phenylC₁₋₄alkyl group, in which the phenyl group is optionally substituted by oneor more C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxy groups or halogen atoms, withthe proviso that R⁵ does not represent a hydrogen atom when R¹represents a group --CO₂ R⁵ or --SO₂ R⁵);

one of the groups represented by R², R³ and R⁴ is a hydrogen atom or aC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or phenylC₁₋₃ alkyl group,and each of the other two groups, which may be the same or different,represents a hydrogen atom or a C₁₋₆ alkyl group;

Q represents a hydrogen atom or a halogen atom or a hydroxy, C₁₋₄alkoxy, phenylC₁₋₃ alkoxy or C₁₋₆ alkyl group or a group --NR⁷ R⁸ or--CONR⁷ R⁸ (wherein R⁷ and R⁸, which may be the same or different, eachrepresents a hydrogen atom or a C₁₋₄ alkyl or C₃₋₄ alkenyl group, ortogether with the nitrogen atom to which they are attached form asaturated 5 to 7 membered ring);

and physiologically acceptable salts and solvates thereof.

In addition, published European Patent Specification No. 200444describes inter alia azabicyclo 3-indazole carboxylic acid ester andamide derivatives which may be represented by the general formula:##STR4## wherein X represents CO and Y represents NH or O, or Xrepresents NH and Y represents CO;

R₁ represents hydrogen, halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₇ acyl, C₁₋₇ acylamino, C₁₋₆ alkylsulphonylamino, N-(C₁₋₆alkylsulphonyl)-N-C₁₋₄ alkylamino, C₁₋₆ alkylsulphinyl, hydroxy, nitroor amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino orN-(aminosulphonyl)-C₁₋₄ -alkylamino optionally N-substituted by one ortwo groups selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkylC₁₋₄ alkyl, phenyl or phenylC₁₋₄ alkyl groups or optionallyN-disubstituted by C₄₋₅ polymethylene;

R₃ represents hydrogen, C₁₋₆ alkyl, C₃₋₇ alkenylmethyl, or phenyl orphenylC₁₋₄ alkyl in which the phenyl group may optionally besubstituted; and

R₂ represents an azabicyclo group of the formula ##STR5## wherein n is 2or 3; p and q are each independently 1 to 3; and R₄ or R₅ representsC₁₋₇ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylC₁₋₂ alkyl or (CH₂)_(t) R₆(where t is 1 or 2, and R₆ is an optionally substituted thienyl,pyrrolyl, furyl or phenyl group).

We have now found a novel group of compounds which differ in structurefrom those described previously, and which are potent antagonists of theeffect of 5-HT at 5-HT `neuronal` receptors.

Thus, in one aspect the present invention provides a ketone of thegeneral formula (I): ##STR6## and physiologically acceptable salts andsolvates thereof, wherein R¹ and R², which may be the same or different,each represents a hydrogen atom or a C₁₋₆ alkyl group;

Im represents an imidazolyl group of formula: ##STR7## wherein one ofthe groups represented by R³, R⁴ and R⁵ is a hydrogen atom or a C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl or phenylC₁₋₃ alkyl group,and each of the other two groups, which may be the same or different,represents a hydrogen atom or a C₁₋₆ alkyl group; and A is a group ofthe formula (a), (b), (c), (d), (e), (f) or (g): ##STR8## wherein R⁶ andR⁷, which may be the same or different, and may be attached to eitherthe same or different fused rings of the naphthalene moiety, eachrepresents a hydrogen atom, a halogen atom, or a hydroxy, C₁₋₄ alkoxy,C₁₋₄ alkyl or C₁₋₄ alkylthio group, and one of R⁶ and R⁷ may alsorepresent a group --NR⁸ R⁹ (wherein R⁸ and R⁹, which may be the same ordifferent, each represents a hydrogen atom or a C₁₋₄ alkyl group, ortogether with the nitrogen atom to which they are attached form asaturated 5 to 7 membered ring);

R¹⁰ represents a hydrogen atom, a halogen atom, or a hydroxy, C₁₋₄alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylthio, nitro or phenyl group, or a group--NR⁸ R⁹ (wherein R⁸ and R⁹ are as defined previously);

R¹¹ represents a hydrogen atom, or a C₁₋₄ alkoxy or C₁₋₄ alkyl group;

R¹² represents a hydrogen atom, a halogen atom or a C₁₋₄ alkoxy group;

or, when R¹⁰ represents a hydrogen atom, R¹¹ and R¹² may be attached toadjacent carbon atoms and form the group --O(CH₂)_(n) O-- where n is 1or 2;

R¹³ represents a hydrogen atom, a halogen atom, or a hydroxy, C₁₋₄alkoxy or C₁₋₄ alkyl group or a group --NR⁸ R⁹ (wherein R⁸ and R⁹ are asdefined previously);

R¹⁴ represents a hydrogen atom, a halogen atom, or a C₁₋₄ alkyl orphenyl group;

D represents an oxygen atom or a sulphur atom;

R¹⁵ represents a hydrogen atom, or a C₁₋₄ alkyl or phenyl group;

R¹⁶ represents a hydrogen atom, a halogen atom or a C₁₋₄ alkyl group;with the provisos that when the group --COCR¹ R² CH₂ Im is attached atthe 3-position of the group (e), R¹⁴ represents a hydrogen atom, ahalogen atom or a C₁₋₄ alkyl group, and R¹⁶ represents a hydrogen atomor a C₁₋₄ alkyl group;

E represents an oxygen atom or a sulphur atom, or a group NR¹⁷ wherein

R¹⁷ represents a hydrogen atom or a C₁₋₆ alkyl group;

R¹⁸ represents a hydrogen atom or a group selected from C₁₋₆ alkyl, C₃₋₆alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,phenyl, phenylC₁₋₃ alkyl, --CO₂ R¹⁹, --COR¹⁹, --CONR¹⁹ R²⁰ or --SO₂ R¹⁹(wherein R¹⁹ and R²⁰, which may be the same or different, eachrepresents a hydrogen atom, a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or aphenyl or phenylC₁₋₄ alkyl group, in which the phenyl group isoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxygroups or halogen atoms, with the proviso that R¹⁹ does not represent ahydrogen atom when R¹⁸ represents a group --CO₂ R¹⁹ or --SO₂ R¹⁹);

R²¹ represents a hydrogen atom or a halogen atom or a hydroxy, C₁₋₄alkoxy, phenylC₁₋₃ alkoxy or C₁₋₆ alkyl group or a group --NR²² R²³ or--CONR²² R²³ (wherein R²² and R²³, which may be the same or different,each represents a hydrogen atom or a C₁₋₄ alkyl or C₃₋₄ alkenyl group,or together with the nitrogen atom to which they are attached form asaturated 5 to 7 membered ring);

V, W, X and Y each independently represent a nitrogen atom or the group--CH--, and Z represents a nitrogen atom or the group --CR²⁴ (where R²⁴represents a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₇cycloalkyl, phenyl or phenylC₁₋₃ alkyl group), with the proviso that oneand only one of V, W, X, y and Z represents a nitrogen atom; and when Arepresents a group of formula (g), the group --COCR¹ R² CH₂ Im isattached at either the 2- or 4-position of the indole moiety.

In the group of formula (a), the substituent --COCR¹ R² CH₂ Im isattached at any available position of the naphthalene moiety. In thegroup of formula (c), one of the substituents R¹⁴ and --COCR¹ R² CH₂ Imis at the 2-position and the other is at the 3-position of thebenzofuran or benzothiophene moiety. In the group of formula (d), one ofthe substituents R¹⁴ and --COCR¹ R² CH₂ Im is at the 2, 3, or4-position, and the other is at either of the two remaining available 2,3 or 4-positions of the quinoline moiety. In the group of formula (e),one of the substituents R¹⁶ and --COCR¹ R² CH₂ Im is at the 2-positionof the furan, thiophene or pyrrole ring, and the other is at the3-position.

In the group of formula (b), the substituents R¹⁰, R¹¹ and R¹² may be atany available position of the phenyl moiety. In the group of formula(c), the substituent R¹³ may be at the 4, 5, 6 or 7-position of thebenzofuran or benzothiophene moiety, and, in the group of formula (d),the substituent R¹³ may be at the 5, 6, 7 or 8-position of the quinolinemoiety. In the group of formula (f), the substituent R²¹ may be attachedto any available carbon atom of the six membered ring.

According to one aspect, the invention provides compounds of formula (I)wherein A represents a group (a) as defined in formula (I) (R¹, R² andIm being as defined in formula (I)).

According to another aspect, the invention provides compounds of formula(I) wherein A represents a group (b) as defined in formula (I) (R¹, R²and Im being as defined in formula (I)).

According to yet another aspect, the invention provides compounds offormula (I) wherein A represents a group (c) as defined in formula (I)(R¹, R² and Im being as defined in formula (I)).

According to a further aspect, the invention provides compounds offormula (I) wherein A represents a group (f) as defined in formula (I)(R¹, R² and Im being as defined in formula (I)).

According to a yet further aspect, the invention provides compounds offormula (I) wherein A represents a group (g) as defined in formula (I),wherein the group --COCR¹ R² CH₂ Im is attached at the 2-position of theindole moiety (R¹, R² and Im being as defined in formula (I)).

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with organic or inorganicacids for example, hydrochlorides, hydrobromides, sulphates, alkyl- orarylsulphonates (e.g. methanesulphonates or p-toluenesulphonates),phosphates, acetates, citrates, succinates, tartrates, fumarates andmaleates. The solvates may, for example, be hydrates.

All optical isomers of compounds of general formula (I) and theirmixtures including the racemic mixtures thereof, and all the geometricisomers of compounds of formula (I), are embraced by the invention.

Referring to the general formula (I), a C₁₋₄ alkyl group (as such, or aspart of a C₃₋₇ cycloalkyl C₁₋₄ alkyl group), may be a straight chain orbranched chain alkyl group, for example, methyl, ethyl, propyl,prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl, and a C₁₋₆ alkyl groupmay also be, for example, a pentyl, pent-3-yl or hexyl group. An alkenylgroup may be, for example, a propenyl or butenyl group. An alkynyl groupmay be, for example, a prop-2-ynyl or oct-2-ynyl group.

It is understood that when R⁴ or R¹⁸ represents a C₃₋₆ alkenyl group orR¹⁸ represents a C₃₋₁₀ alkynyl group, or R²² or R²³ represents a C₃₋₄alkenyl group, the double or triple bond may not be adjacent to thenitrogen atom.

A phenylC₁₋₃ alkyl group (as such or as part of a phenylC₁₋₃ alkoxygroup) may be, for example, a benzyl, phenethyl or 3-phenylpropyl group.A C₃₋₇ cycloalkyl group (as such or as part of a cycloalkylalkyl group)may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl group. A C₁₋₄ alkoxy group may be, for example, a methoxygroup. A halogen atom may be, for example, a fluorine, chlorine orbromine atom.

A preferred class of compounds of formula (I) is that in which R¹ and R²each represent a hydrogen atom.

Another preferred class of compounds of formula (I) is that in which R³,R⁴ and R⁵ each independently represents a hydrogen atom or a C₁₋₄ alkyl(e.g. methyl) group. A further preferred class of compounds is thatwherein R³ and R⁴ each represent a hydrogen atom, and R⁵ is a C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl, or phenylC₁₋₃ alkyl group,more particularly C₁₋₃ alkyl (e.g. methyl).

Another preferred class of compounds of formula (I) is that in which Ais a group (a), and R⁶ and R⁷ each represent a hydrogen atom. A furtherpreferred class of compounds of formula (I) in which A is a group (a) isthat in which one of R⁶ and R⁷ represents a halogen atom (e.g.fluorine), or a hydroxy, C₁₋₄ alkoxy (e.g. methoxy) or C₁₋₄ alkyl (e.g.methyl) group, and the other is a hydrogen atom.

Another preferred class of compounds of formula (I) is that in which Ais a group (b), and R¹⁰ represents an amino group or, more preferably, ahydrogen atom or a C₁₋₄ alkyl (e.g. methyl), C₁₋₄ alkoxy (e.g. methoxy)or phenyl group, R¹¹ represents a C₁₋₄ alkoxy (e.g. methyl) group or,more preferably, a hydrogen atom or a C₁₋₄ alkyl (e.g. methyl) group,and R¹² represents a halogen atom (e.g. chlorine) or, more preferably, ahydrogen atom.

Another preferred class of compounds of formula (I) is that in which Ais a group (c) or (d), and R¹³ represents a hydrogen atom, and R¹⁴represents a hydrogen atom or a C₁₋₄ alkyl (e.g. methyl) group. When Ais a group (d), the group --COCR¹ R² CH₂ Im is preferably attached atthe 4-position of the quinoline moiety.

Another preferred class of compounds of formula (I) is that in which Ais a group (e), and two of R¹⁴, R¹⁵ and R¹⁶ represent a C₁₋₄ alkyl (e.g.methyl) group, and the other represents a hydrogen atom. When Erepresents the group NR¹⁷, R¹⁷ is preferably a C₁₋₄ alkyl (e.g. methyl)group. A further preferred class of compounds of formula (I) in which Ais a group (e) is that in which the group --COCR¹ R² CH₂ Im is attachedat the 3-position of the heterocycle.

Another preferred class of compounds of formula (I) is that in which Ais a group (f), and one of Y and Z represents a nitrogen atom. When Y isa nitrogen atom, R²⁴ is preferably a hydrogen atom. A further preferredclass of compounds of formula (I) is which A is a group (f) is that inwhich R¹⁸ represents a hydrogen atom or, more preferably, a C₁₋₆ alkyl(e.g. methyl) group. A yet further preferred class of compounds offormula (I) in which A is a group (f) is that in which R²¹ represents ahydrogen atom.

Another preferred class of compounds of formula (I) is that in which Ais a group (g), and R¹⁷ represents a C₁₋₄ alkyl (e.g. methyl) group. Afurther preferred class of compounds of formula (I) in which A is agroup (g) is that in which R¹⁵ represents a hydrogen atom.

Particularly preferred meanings of the group A are those represented bythe formulae (a), (c) wherein the group --COCR¹ R² CH₂ Im is attached atthe 3-position of the benzofuran or benzothiophene moiety, (f), and (g)wherein the group --COCR¹ R² CH₂ Im is attached at the 4-position of theindole moiety.

Particularly preferred compounds according to the invention are:

3-(5-methyl-1H-imidazol-4-yl)-1-(1-naphthalenyl)-1-propanone;

1-(4-methoxy-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone;

1-(2-hydroxy-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone;

1-(benzo[b]thien-3-(5-methyl-1H-imidazol-4-yl)-1-propanone;

3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indazol-3-yl)-1-propanone;

3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-4-yl)-1-propanone;and their physiologically acceptable salts and solvates.

Compounds of the invention are potent and selective antagonists of 5-HTinduced responses of the rat isolated vagus nerve preparation and thusact as potent and selective antagonists of the `neuronal` 5-HT receptortype located on primary afferent nerves. Receptors of this type are nowdesignated as 5-HT₃ receptors. Such receptors are also present in thecentral nervous system. 5-HT occurs widely in the neuronal pathways inthe central nervous system and disturbance of these 5-HT containingpathways is known to alter behavioural syndromes such as mood,psychomotor activity, appetite and memory.

Compounds of formula (I), which antagonise the effect of 5HT at 5-HT₃receptors, are useful in the treatment of conditions such as psychoticdisorders (e.g. schizophrenia and mania); anxiety; and nausea andvomiting, particularly that associated with cancer chemotherapy andradiotherapy. Compounds of formula (I) are also useful in the treatmentof gastric stasis; symptoms of gastrointestinal dysfunction such asoccur with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence andirritable bowel syndrome; migraine; and pain. Compounds of formula (I)may also be used in the treatment of dependency on drugs and substancesof abuse, depression, and dementia and other cognitive disorders.

According to another aspect, the invention provides a method oftreatment of a human or animal subject suffering from a psychoticdisorder such as schizophrenia or mania; or from anxiety; nausea orvomiting, particularly that associated with cancer chemotherapy andradiotherapy; gastric stasis; symptoms of gastrointestinal dysfunctionsuch as dyspepsia, reflux oesophagitis, peptic ulcer, flatulence andirritable bowel syndrome; migraine; pain; dependency on drugs orsubstances of abuse; depression; or dementia and other cognitivedisorders, which comprises administering an effective amount of acompound of formula ((I) or a physiologically acceptable salt or solvatethereof.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound selected from ketone derivativesof the general formula (I), their physiologically acceptable salts andsolvates (e.g. hydrates), for use in human or veterinary medicine, andformulated for administration by any convenient route.

Such compositions may be formulated in conventional manner using one ormore physiologically acceptable carriers and/or excipients.

Thus the compounds according to the invention may be formulated fororal, buccal, parenteral, rectal or transdermal administration or in aform suitable for administration by inhalation or insufflation (eitherthrough the mouth or the nose).

For oral administration, the pharmaceutical compositions may take theform of, for example tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maze starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose; fillers (e.g. lactose, microrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by injection e.g. by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds ofthe invention may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously, transcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds of the invention may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble slat.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs or a nebuliser, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluorethane, carbon dioxide orother suitable gas. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of a compound ofthe invention and a suitable powder base such as lactose or starch.

For intranasal administration, the compounds according to the inventionmay be formulated as solutions for administration via a suitable meteredor unit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

The compounds of formula (I) may also be administered in combinationwith other therapeutic agents. Thus, for example, in the treatment ofgastric stasis, symptoms of gastrointestinal dysfunction and nausea andvomiting, the compounds of formula (I) may be administered incombination with antisecretory agents such as histamine H₂ -receptorantagonists (e.g. ranitidine, sufotidine or1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]amino]-1H-1,2,4-triazole-3-methanol)or H⁺ K⁺ ATPase inhibitors (e.g. omeprazole).

A proposed dose of the compounds of the invention for administration toman (of approximately 70 Kg body weight) is 0.001 to 100 mg, preferably0.01 to 50 mg, most preferably 0.5 to 20 mg of the active ingredient perunit dose (expressed as the weight of free base) which could beadministered, for example, 1 to 4 times per day. The dose will depend onthe route of administration and the condition being treated. It will beappreciated that it may be necessary to make routine variation to thedosage depending on the age and weight of the patient as well as theseverity of the condition to be treated.

According to another aspect of the invention, compounds of generalformula (I) and physiologically acceptable salts or solvates thereof maybe prepared by the general methods outlined hereinafter. In thefollowing description, the groups A, R¹, R² and Im are as defined forcompounds of general formula (I) unless otherwise stated.

According to a first general process (A) a compound of general formula(I), wherein R² represents a hydrogen atom, may be prepared byhydrogenation of a compound of formula (II): ##STR9## or a protectedderivative thereof, followed where necessary by removal of anyprotecting groups.

Hydrogenation according to general process (A) may be effected usingconventional procedures, for example using hydrogen in the presence of anoble metal catalyst (e.g. palladium, Raney nickel, platinum orrhodium). The catalyst may be supported on, for example, charcoal oralumina, or alternatively a homogeneous catalyst such astris(triphenylphosphine)rhodium chloride may be used. The hydrogenationwill generally be effected in a solvent such as an alcohol (e.g.methanol or ethanol), an ether (e.g. dioxan), or an ester (e.g. ethylacetate), or in a mixture of an alcohol and either a hydrocarbon (e.g.toluene) or a halogenated hydrocarbon (e.g. dichloromethane), and at atemperature in the range-20° to +100° C., preferably 0° to 50° C.

Compounds of formula (II) are novel compounds and constitute a furtheraspect of the invention. In addition, certain compounds of formula (II)are antagonists of the effect of 5-HT at 5HT₃ receptors. A particulargroup of compounds of formula (II) is that in which A is a group (a) asdefined in formula (I) (R¹ and Im being as defined in formula (I)). Apreferred compound of formula (II) is(E)-3-(5-methyl-1HH-imidazol-4-yl)-1-(1-naphthalenyl)-2-propen-1-one.

According to another general process (B), a compound of general formula(I) may be converted into another compound of formula (I) usingconventional techniques. Such conventional techniques includehydrogenation, alkylation, acylation and acid-catalysed cleavage usingprotection and deprotection where necessary.

Thus, according to one embodiment of the interconversion process (B),hydrogenation may be used to convert an alkenyl or an alkynylsubstituent into an alkyl substituent, or an alkynyl into an alkenylsubstituent, or a benzyloxy substituent into a hydroxyl group.Hydrogenation according to general process (B) may be effected usingconventional procedures, for example as described above for generalprocess (A).

Akylation according to process (B) may be used to effect C-, N- orO-alkylation at any appropriate position in the molecule, and the term`alkylation` also includes the introduction of other group such ascycloakyl, alkenyl or phenalkyl groups.

Thus, for example, a compound of formula (I) in which one or both of R¹and R² represents a C₁₋₆ alkyl group may be prepared by alkylating thecorresponding compound of formula (I) in which one or both of R¹ and R²represent a hydrogen atom, or a compound in which one or both of R³ andR⁴ represent a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl or phenyl C₁₋₃alkyl group may be prepared by alkylating the corresponding compound offormula (I) in which one or both of R³ and R⁴ represent a hydrogen atom.

The above alkylation reactions may be effected using the appropriatealkylating agent selected from compounds of formula R²⁵ L where R²⁵represents a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, C₃₋₁ alkynyl,C₃₋₇ cycloalkylC₁₋₄ alkyl, or phenylC₁₋₃ alkyl group, and L represents aleaving atom or group such as a halogen atom (e.g. chlorine, bromine oriodine), an acyloxy group (e.g. trifluoroacetyloxy or acetoxy), or asulphonyloxy group (e.g. trifluoromethanesulphonyloxy,p-toluenesulphonyloxy or methanesulphonyloxy); or a sulphate of formula(R²⁵)₂ SO₄.

The alkylation reaction is conveniently carried out in an inert organicsolvent such as a substituted amide (e.g. dimethylformamide), an ether(e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. toluene),preferably in the presence of a base. Suitable bases include, forexample, alkali metal hydrides (e.g. sodium hydride), alkali metalamides (e.g. sodium amide or lithium diisopropylamide), alkali metalcarbonates (e.g. sodium carbonate) or an alkali metal alkoxide (e.g.sodium or potassium methoxide, ethoxide or t-butoxide). The reaction mayconveniently be effected at a temperature in the range -80° to +100° C.,preferably -80° to +50° C.

According to another embodiment of general process (B), a compound offormula (I) wherein R¹⁸ represents -CO₂ R¹⁹, --COR¹⁹, --CONR¹⁹ R²⁰ or-SO₂ R¹⁹ may be prepared by acylating or sulphonylating as appropriate,a compound of formula (I) wherein R¹⁸ represents a hydrogen atom. Theacylation/sulphonylation reactions may be effected using an appropriateacylating/sulphonylating agent according to conventional procedures, forexample, as described in published European Patent Specification No.210840.

According to a yet further embodiment of general process (B), a compoundof formula (I) in which the group A contains a hydroxyl substituent maybe prepared from the corresponding compound of formula (I) in which thegroup A is substituted by a C₁₋₄ alkoxy or benzyloxy group, byacid-catalysed cleavage. The reaction may be effected using a Lewis acidsuch as known tribromide or aluminium trichloride, in a solvent such asa halogenated hydrocarbon (e.g. dichloromethane). The reactiontemperature may conveniently be in the range -80° to +100° C.

It should be appreciated that in the above transformations it may benecessary or desirable to protect any sensitive groups in the moleculeof the compound in question to avoid undesirable side reactions. Forexample, it may be necessary to protect the keto group, for example, asa ketal or a thioketal, It may also be necessary to protect theimidazole nitrogen atom, or any of the indole or indazole nitrogen atomsthat may be present, for example with an arylmethyl (e.g. benzyl ortrityl), alkyl (e.g. t-butyl), alkoxymethyl (e.g. methoxymethyl), acyl(e.g. benzyloxycarbonyl) or a sulphonyl (e.g. N,N-dimethylaminosulphonylor p-toluenesulphonyl) group. It may also be necessary to protect anyhydroxyl groups which may be present in the group A, for example with anarylmethyl (e.g. benzyl or trityl) group. When a hydroxy substituent inthe group A is attached to the carbon atom adjacent to the position ofattachment of the group --COCR¹ R² CH₂ Im, this may be protected bycyclisation onto the CH₂ group of the --COCR¹ R² CH₂ Im moiety.

Thus according to another general process (C), a compound of generalformula (I) may be prepared by the removal of any protecting groups froma protected form of a compound of formula (I). Deprotection may beeffected using conventional techniques such as those described in`Protective Groups in Organic Synthesis` by T. W. Greene (John Wiley andSons, 1981).

For example a ketal such as an alkyleneketal group may be removed bytreatment with a mineral acid such as hydrochloric acid. A thioketalgroup may be cleaved by treatment with a mercuric salt, (e.g. mercuricchloride), in a suitable solvent, such as ethanol. An arylmethylN-protecting group may be cleaved by hydrogenolysis in the presence of acatalyst (e.g. palladium on charcoal) and a trityl group may also becleaved by acid hydrolysis (e.g. using dilute hydrochloric or aceticacid). An alkoxyalkyl group may be removed using a Lewis acid such asboron tribromide. An acyl group may be removed by hydrolysis underacidic or basic conditions (e.g. using hydrogen bromide or sodiumhydroxide). A sulphonyl group may be removed by alkaline hydrolysis. Anarylmethyl OH-protecting group may be cleaved under acidic conditionse.g. with dilute acetic acid, hydrobromic acid or boron tribromide) orby hydrogenolysis in the presence of a catalyst (e.g. palladium oncharcoal). When a hydroxy substituent on the group A is protected bycyclisation onto the group --COCR¹ R² CH₂ Im, deprotection may beeffected by treatment with a base (e.g. potassium hydroxide).

A compound of formula (II) or a protected derivative thereof, may beprepared by condensing a compound of formula (III): ##STR10## or aprotected derivative thereof, with a compound of formula (IV):

    OHC-Im                                                     (IV)

or protected derivative thereof, in the presence of a base such as analkali metal hydroxide or alkoxide, followed where necessary by removalof any protecting groups.

The reaction may conveniently be effected using an alkali metalhydroxide (e.g. sodium or potassium hydroxide) in an alcohol (e.g.methanol or ethanol) or water, or mixtures thereof, or using an alkalimetal alkoxide (e.g. sodium ethoxide or potassium t-butoxide) in thecorresponding alcohol (e.g. ethanol or t-butanol) or in an inert solventsuch as an ether (e.g. Tetrahydrofuran), at a temperature in the rangeof 0° to 100° C.

Alternatively, the condensation between compounds of formulae (III) and(IV) or protected derivatives thereof may be carried out in the presenceof a base such as an alkali metal amide (e.g. lithium diisopropylamide)in an inert solvent such as an ether (e.g. tetrahydrofuran), followed bydehydration, and removal of any protecting groups where necessary.

The dehydration process may be effected using conventional methods, forexample by using an organic or mineral acid (e.g. p-toluenesulphonic orhydrochloric acid) in a suitable solvent such as an ther (e.g.tetrahydrofuran), an alcohol (e.g. methanol), or glacial acetic acid, ata temperature in the range of 0° to 100° C.

Compounds of formula (III) are either known or may be prepared fromknown compound by conventional methods, such as, for example, treatingthe corresponding carboxylic acid with an appropriate alkyllithiumreagent R¹ CH₂ Li.

Compounds of formula (IV) may be prepared as described in publishedEuropean Patent Specification No. 242973.

Where it is desired to isolate a compound of the invention as a salt,for example a physiologically acceptable salt, this may be achieved byreacting the compound or formula (I) in the form of the free base withan appropriate acid, preferably with an equivalent amount, in a suitablesolvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g.ethyl acetate) or an ether (e.g. tetrahydrofuran).

Physiologically acceptable salts may also be prepared from other salts,including other physiologically acceptable salts, of the compound offormula (I) using conventional methods.

Individual enantiomers of the compounds of the invention may be obtainedby resolution of a mixture of enantiomers (e.g. a racemic mixture) usingconventional means, such as an optically active resolving acid; see forexample `Stereochemistry of Carbon Compounds` by E. L. Eliel (McGrawHill, 1962) and `Tables of Resolving Agents` by S. H. Wilen.

The various general methods described above may be used for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not effect groups in the molecule which are desired in the finalproduct.

The invention is further illustrated by the following Intermediates andExamples. All temperatures are in 0° C. Thin layer chromatography(t.l.c.) was carried out on silica, and flash column chromatography(FCC) and short-path column chromatography (SPCC) on silica (Merck 9385and 7747 respectively). Solvent System A as used for chromatographydenotes dichloromethane:ethanol:0.88 ammonia solution and System Bdenotes ethyl acetate:hexane. Organic extracts were dried over sodiumsulphate or magnesium sulphate. The following abbreviations are used:THF-tetrahydrofuran, DMF-dimethylformamide.

Intermediate 1 is5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde. Intermediate2 1-(5-fluoro-1-naphthalenyl)ethanone

Methyl lithium (1.4M solution in ether; 6.6 ml) was added dropwise to astirred solution of 5-fluoro-1-naphthalene carboxylic acid (870 mg) indry THF (15 ml) at -78° under nitrogen. The reaction mixture was allowedto warm to room temperature over 2 h and was treated with 2N sodiumhydroxide (60 ml). The mixture was extracted with ether (2×30 ml), andthe combined, dried organic extracts were evaporated to give the titlecompound (865 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.3.

Intermediate 3 1-(1,2,4-Trimethyl-1H-pyrrol-3-yl)ethanone

A solution of 3-acetyl-2,4-dimethylpyrrole (2.0 g) in dry DMF (30 ml)was added dropwise, with stirring, to a suspension of sodium hydride(78% dispersion in oil; 565 mg) in dry DMF (15 ml) at 0° under nitrogenand stirring was continued at room temperature for 1 h. Iodomethane(1.14 ml) was added dropwise at 0° and stirring was continued for 1.5 h.The suspension was evaporated, treated with 8% aqueous sodiumbicarbonate (80 ml) and extracted with ethyl acetate (2×80 ml). Thecombined, dried organic extracts were evaporated to give a solid (2.1 g)which was dissolved in dichloromethane (20 ml) and adsorbed onto silicagel (Merck 7734, 6 g). This was applied to an FCC column and elutionwith System B (1:3) afforded the title compound (1.89 g) as crystals,m.p. 68°-70°.

Intermediate 4 1-(1-Methyl-1H-indazol-3-yl)ethanone

Methyl lithium (1.58M solution in ether; 13.8 ml) was added dropwise toa stirred, cold (-60°) solution of 1-methyl-1H-indazole-3-carboxylicacid (1.77 g) in dry THF (60 ml) under nitrogen and stirring wascontinued while warming to 0° over 2 h. The reaction mixture wasquenched with saturated ammonium chloride solution (50 ml), and thelayers were separated. The aqueous layer was further extracted withdichloromethane (2×50 ml) and the combined organic layers were washedwith brine (2×50 ml), dried and evaporated in vacuo. The residual solid(1.8 g) was purified by FCC eluting with System B (1:4) to give thetitle compound (1.3 g), m.p. 86°-88°.

Intermediate 5 1-(6-Fluoro-1-naphthalenyl)ethanone

Methyl lithium (1.59M solution in ether; 4.2 ml) was added dropwise to astirred solution of 6-fluoro-1-naphthalene carboxylic acid (640 mg) indry THF (10 ml) at -78° under nitrogen. The solution was stirred at -78°for 2 h and was slowly allowed to warm to -15°. The solution wasquenched with saturated aqueous ammonium chloride (1 ml) and partitionedbetween 2N sodium hydroxide (25 ml) and ethyl acetate (25 ml). Theorganic phase was dried and evaporated to give the title compound (404mg) as an oil, t.l.c. (System B, 1:6) Rf 0.2.

Intermediate 6(E)-3-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(2-naphthalenyl)-2-propen-1-one

A solution of 2-acetylnaphthalene (0.965 g) and Intermediate 1 (2.0 g)in ethanol (40 ml) was treated with a solution of potassium hydroxide(2.5 g) in water (15 ml), and the mixture was stirred overnight. Theresulting precipitate was filtered off, recrystallised fromethanol/water (6:1; 50 ml) and dried (in vacuo, 95°, 2 h) to give thetitle compound (1.90 g), m.p. 197°-199°.

Concentration of the mother liquors in vacuo followed by dilution withwater afforded a second crop of the title compound (0.59 g), m.p.194°-197°.

Intermediate 7(E)-3-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-phenyl-2-propen-1-one

A solution of acetophenone (681 mg) and Intermediate 1 (2.0 g) inethanol (40 ml) was treated with a solution of potassium hydroxide (2.48g) in water (15 ml), and the mixture was stirred overnight. Theresulting precipitate was filtered off, recrystallised fromethanol/water (4:1; 50 ml) and dried (in vacuo, 95°, 2 h) to give thetitle compound (2.30 g) as crystals, m.p. 209°-211°.

Intermediate 8(E)-3-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(1-naphthalenyl)-2-propen-1-one

A solution of 1-acetylnaphthalene (0.965 g) and Intermediate 1 (2.0 g)in ethanol (40 ml) was treated with a solution of potassium hydroxide(2.5 g) in water (15 ml), and was stirred for 36 h at room temperature.The mixture was filtered and the solid was recrystallised twice fromethanol (30 ml) to give the title compound (1.17 g) as needles, m.p.184°-186°. The mother liquors were combined and evaporated in vacuo toleave a solid (ca. 1.6 g) which was purified by SPCC eluting with SystemB (3:7) to give a second crop of the title compound (0.58 g), m.p.184°-186°.

Intermediate 9(E)-3-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(4-quinolinyl)-2-propen-1-one

Potassium hydroxide (1.8 g) in water (5 ml) was added to a stirredsuspension of 4-acetylquinoline (700 mg) and Intermediate 1 (1.44 g) inabsolute ethanol (30 ml). After 2 h the reaction mixture was partitionedbetween water (150 ml) and dichloromethane (3×150 ml) and the combined,dried organic layers were evaporated in vacuo to leave a foam (2.2 g)which was purified by FCC eluting with ether→dichloromethane/ethanol(95:5) to give the title compound (550 mg), t.l.c. (ether) Rf 0.11.

Intermediate 10(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(1-naphthalenyl)-2-propen-1-onemaleate

A solution of(E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-(1-naphthalenyl)-2-propen-1-one(1.0 g) in a mixture of water (10 ml, THF (10 ml) and acetic acid (10ml) was heated at reflux under nitrogen for 1 h. The cooled reactionmixture was partitioned between ethyl acetate (100 ml; discarded) and0.4N hydrochloric acid (2×75 ml). The combined acidic layers werebasified with potassium carbonate (to pH8) and extracted withdichloromethane (3×50 ml). The combined dichloromethane extracts weredried and evaporated in vacuo to give the free base of the titlecompound (0.51 g) as a solid. This was dissolved in hot methanol (15ml), and a solution of maleic acid (0.23 g) in methanol (2 ml) was addedwith stirring. Cooling precipitated the title compound (0.62 g), m.p.170°-173° (decomp.).

Analysis Found: C,67.0; H,4.8; N,7.4; C₁₇ H₁₄ N₂ O.C₄ H₄ O₄ requiresC,66.7; H,4.8; N,7.4%.

Intermediates 11, 12 and 13 were all prepared in a similar manner toIntermediate 10 by deprotection of the appropriate tritylated enone,followed by salt formation.

Intermediate 11(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(2-naphthalenyl)-2-propen-1-onemaleate

The deprotection of(E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(2-naphthalenyl)-2-propen-1-one (1.25 g) followed by maleate formationgave the title compound (0.75 g), m.p. 190°-191° (decomp.).

Intermediate 12(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-phenyl-2-propen-1-one maleate

The deprotection of(E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-phenyl-2-propen-1-one(1.25 g) gave a solid which was triturated with ether (50 ml) to givethe free base of the title compound (0.40 g). This was dissolved inmethanol (20 ml), and a solution of maleic acid (0.23 g) in ethanol (2ml) was added with stirring. After dilution with ethyl acetate (10 ml)the mixture was filtered to give the title compound (0.56 g) as acrystalline solid, m.p. 178°-179°.

Intermediate 133-(5-Methyl-1H-imidazol-4-yl)-1-(4-quinolinyl)-2-propen-1-one succinate

The deprotection of(E)-3-[5-methyl-1-(triphenymethyl)-1H-imidazol-4-yl]-1-(4-quinolinyl)-2-propen-1-one(550 mg) gave the free base of the title compound (275 mg) which wasdissolved in absolute ethanol (3 ml) and a solution of succinic acid(127 mg) in methanol (1 ml) was added.

Concentration of the solution to ca. 0.5 ml and dilution with dry etherafforded the title compound (225 mg) as a solid, m.p. 154°-156°.

Intermediate 141-(5-Fluoro-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A solution of potassium hydroxide (390 mg) in methanol (5 ml) was addedto a suspension of 1-(5-fluoro-1-naphthalenyl)ethanone (830 mg) andIntermediate 1 (1.55 g) in methanol (20 ml) and the mixture was heatedat reflux for 4 h. The solution was treated with THF (25 ml), water (25ml) and acetic acid (10 ml) and was then heated at reflux for a further2 h. The solution was added cautiously to 8% aqueous sodium bicarbonate(170 ml) and was extracted with dichloromethane (2×50 ml). The extractswere dried and evaporated to give an oil which was purified by FCCeluting with System A (100:3:0.3)→(100:10:1) to give the title compound(1.06 g) as a foam, t.l.c. (System A, 100:10:1) Rf 0.4.

Intermediate 15(E)-1-(2-Methoxyphenyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A mixture of 2'-methoxyacetophenone (0.85 g), Intermediate 1 (2.0 g) andpotassium hydroxide (0.5 g) in methanol (25 ml) was stirred at 23° forca. 70 h. The mixture was diluted with acetic acid (20 ml), water (20ml) and ethanol (80 ml) and heated on a steam bath for 2 h. Theresulting mixture was partitioned between 1M hydrochloric acid (3×75 ml)and ethyl acetate (200 ml; discarded). The aqueous layer was basifiedwith potassium carbonate (to pH9) and extracted with ethyl acetate(3×200 ml). The combined, dried organic extracts were evaporated toleave a gum (ca. 1.2 g) which was purified by SPCC eluting with System A(200:8:1) to give the title compound (0.48 g) as a foam, t.l.c. (SystemA, 100:8:1) Rf 0.41.

Intermediate 16(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(3,5-dimethylphenyl)-2-propen-1-one

A mixture of 3,5-dimethylacetophenone (0.5 g) and Intermediate 1 (1.2 g)(0.3 g) in methanol (5 ml), and the mixture was kept at 23° for 3 days.The mixture, from which some crystals had separated, was then stirredwith cooling (0°) for 15 min, filtered and the resultant solid waswashed with cold methanol and dried. This solid (1.1 g) was heated atreflux in a mixture of THF (20 ml), acetic acid (5 ml) and water (5 ml)for 1 h. The mixture was concentrated in vacuo to ca. 10 ml, dilutedwith ethyl acetate (50 ml) and washed with 2N aqueous sodium carbonate(2×50 ml; discarded). The organic phase was evaporated to give a solidwhich was purified by FCC eluting with ethylacetate/methanol/triethylamine (90:10:1) to give the title compound(0.32 g), m.p. 165°-166°.

Intermediate 17 (E)-1-(2-Methyl-3-benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was addedto a solution of Intermediate 1 (2.0 g) and 3-acetyl-2-methylbenzofuran(1.0 g) in methanol (25 ml), and the mixture was stirred at roomtemperature for 5 days. The resultant solid (1.11 g) was filtered offand heated at reflux in a mixture of acetic acid (30 ml), water (30 ml)and THF (30 ml) for 1.5 h. The reaction mixture was poured into 1Nhydrochloric acid (120 ml) and washed with ethyl acetate (120 ml). Theaqueous layer was basified with potassium carbonate (to pH 9), extractedwith dichloromethane (3×120 ml) and the combined extracts were dried andevaporated to give an oil (0.30 g). The ethyl acetate wash wasevaporated to give a solid (ca. 0.90 g) and the two batches werecombined and triturated with ethyl acetate/methanol (19:1) to give thetitle compound (0.34 g) as a solid, m.p. 166°-168°.

Intermediate 18(E)-1-(2-Methylbenzo[b]thien-3-yl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A solution of potassium hydroxide (200 mg) in methanol (2 ml) was addedto a solution of Intermediate 1 (741 mg) and3-acetyl-2-methylbenzo[b]thiophene (400 mg) in methanol (10 ml), and themixture was stirred at room temperature for 16 h. The resultant solid(780 mg) was filtered off and heated at reflux in a mixture of aceticacid (20 ml), water (20 ml) and THF (20 ml) for 1.5 h. The THF wasremoved in vacuo, 1N hydrochloric acid (80 ml) was added and thesolution was washed with ethyl acetate (80 ml; discarded). The aqueouslayer was basified with potassium carbonate (to pH 9) and extracted withdichloromethane (3×80 ml). The combined organic extracts were dried andevaporated to give the title compound (217 mg) as a solid, m.p.154°-156°.

Intermediate 19(E)-1-(3-Benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A mixture of 3-acetylbenzofuran (0.91 g), Intermediate 1 (2.0 g) andpotassium hydroxide (0.50 g) in methanol (15 ml) was stirred at roomtemperature under nitrogen for 4 days. The resultant solid was thentreated according to the method of Intermediate 18 to give a solid whichwas purified by FCC eluting with System A (100:10:1) to give the titlecompound (0.32 g), m.p. 192°-193°.

Intermediate 20(E)-1-[Benzo[b]thien-2-yl]-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was addedto a suspension of 2-acetylbenzo[b]thiophene (1.0 g) and Intermediate 1(2.0 g) in methanol (25 ml), and the mixture was stirred at roomtemperature for 19 h. The suspension was filtered and the collectedsolid was dried in vacuo. The resultant solid (2.33 g) was heated atreflux in a mixture of acetic acid (8 ml), water (5 ml) and THF (25 ml)for 3 h. The reaction mixture was added cautiously to 8% aqueous sodiumbicarbonate (200 ml) and extracted with dichloromethane (3×60 ml). Thecombined organic extracts were dried and evaporated to give a solidwhich was purified by FCC eluting with System A (100:8:0.8) to give thetitle compound as a solid (0.76 g), m.p. 188°-190°.

Intermediate 21(E)-1-(2-Benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A mixture of 2-acetylbenzofuran (0.91 g), Intermediate 1 (2.0 g) andpotassium hydroxide (0.50 g) in methanol (15 ml) was stirred at roomtemperature under nitrogen for 24 h. The suspension was evaporated,treated with water (50 ml) and extracted with dichloromethane (50 ml).The organic extract was dried and evaporated, and the resultant oil washeated at reflux in a mixture of acetic acid/water/THF (1:1:1; 50 ml)for 1 h. The cooled reaction mixture was evaporated and the resultantsolid was treated with 1N hydrochloric acid (70 ml) and extracted withethyl acetate (60 ml; discarded). The aqueous phase was basified with 2Nsodium carbonate (75 ml) and extracted with dichloromethane (2×100 ml).The combined, dried organic extracts were evaporated to give a foam (ca.1.6 g) which was purified by SPCC eluting with System A (945:50:5) togive the title compound (0.82 g) as a foam, t.l.c. (System A, 945:50:5)Rf 0.12.

Intermediate 22(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-2-propen-1-one

A mixture of 1-(1-methyl-1H-indol-2-yl)ethanone (250 mg), Intermediate 1(520 mg) and potassium hydroxide (130 mg) in methanol (7 ml) was heatedat 50° for 20 h under nitrogen. The reaction mixture was treatedaccording to the method of Intermediate 21 to give a solid which waspurified by FCC eluting with System A (912:80:8) to give the titlecompound (337 mg) as crystals, m.p. 222°-224°.

Intermediate 23(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-2-propen-1-one

A solution of potassium hydroxide (250 mg) in methanol (3 ml) was addedto a suspension of Intermediate 1 (1.0 g) and3-acetyl-1,2,4-trimethyl-1H-pyrrole (430 mg) in methanol (12 ml), andthe suspension was stirred at reflux under nitrogen for 65 h. Thereaction mixture was treated according to the method of Intermediate 21to give a foam (670 mg) which was purified by FCC eluting with System A(89:10:1) to give the title compound (580 mg) as a powder, t.l.c.(System A, 89:10:1) Rf 0.28.

Intermediate 24(E)-1-(2,5-Dimethyl-3-furanyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one

A solution of potassium hydroxide (650 mg) in methanol (7 ml) was addedto a suspension of Intermediate 1 (2.60 g) and3-acetyl-2,5-dimethylfuran (1.0 g) in methanol (30 ml), and thesuspension was stirred at room temperature for 5 days. The reactionmixture was treated according to the method of Intermediate 21 to give asolid (1.0 g). This was dissolved in ethanol (50 ml) and adsorbed ontosilica gel (Merck 7734, 3 g) which was then applied to an SPCC column.Elution with System A (189:10:1) gave the title compound as an oil (710mg), t.l.c. (System A, 189:10:1) Rf 0.15.

Intermediate 25(E)-1-(2,5-Dimethyl-3-thienyl)-3-[5-methyl-1H-imidazol-4-yl]-2-propen-1-onehemi-succinate

A mixture of 3-acetyl-2,5-dimethylthiophene (0.43 ml) and Intermediate 1(1.06 g) in ethanol (60 ml) was treated with a solution of potassiumhydroxide (0.8 g) in water (2 ml). The resulting solution was stirred at20° for 21 h and heated on a steam bath for 2 h. The mixture was thencooled to 20°, treated with glacial acetic acid (15 ml) and heated on asteam bath for 2 h. The acidic reaction mixture was cooled (20°) andpartitioned between saturated potassium carbonate solution (250 ml) andethyl acetate (2×250 ml). The combined, dried organic extracts wereevaporated to give a gum (ca.2 g) which was purified by FCC eluting withSystem A (100:8:1) to give a solid (0.55 g). This was dissolved inabsolute ethanol (30 ml) and treated with a solution of succinic acid(0.264 g) in ethanol (30 ml). The resulting solution was concentrated invacuo to ca. 5 ml and diluted with dry ether (50 ml) to precipitate thetitle compound (0.57 g), m.p. 163°-165°.

Intermediate 26(E)-1-(4-Methoxy-1-naphthalenyl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one

A solution of potassium hydroxide (0.6 g) in methanol (5 ml) was addedto a solution of 1-acetyl-4-methoxynaphthalene (0.6 g) and Intermediate1 (1.0 g) in methanol (20 ml) at room temperature and the mixture waskept at 23° under nitrogen for 4 days. The resulting crystals werefiltered off, washed with methanol and dried to give the title compound(1.1 g), m.p. 235°-237°.

Intermediate 27(E)-3-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(2-methyl-1-naphthalenyl)-2-propen-1-one

A mixture of 1-acetyl-2-methylnaphthalene (1.5 g), Intermediate 1 (2.0g) and potassium hydroxide (0.5 g) in methanol (25 ml) was heated at 50°for 24 h, cooled on ice and filtered. The solid was washed with water(100 ml) and dried (75°, in vacuo, 2 h) to give the title compound (2.39g), m.p. 222°-224°.

Intermediate 28(E)-1-[(1,1'-Biphenyl)-3-yl]-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4yl]-2-propen-1-one

A mixture of potassium hydroxide (0.6 g), 3-phenylacetophenone, (0.8 g)and Intermediate 1 (1.44 g) in methanol (25 ml) was kept at 23° for 4days after which time an oil had separated. The supernatant solution wasdecanted off and the residual oil was purified by FCC eluting firstlywith dichloromethane/hexane (4:1), and then with dichloromethane/ether(1:1) to give the title compound (0.9 g) as a foam.

Analysis Found: C,85.6; H,5.8; N,4.95; C₃₈ H₃₀ N₂ O requires C,86.0;H,5.7; N,5.3%.

Intermediate 29(E)-1-(1-Methyl-1H-indazol-3-yl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one

A mixture of 1-(1-methyl-1H-indazol-3-yl)ethanone (0.75 g), Intermediate1 (1.5 g) and potassium hydroxide (0.375 g) in methanol (12.5 ml) wasstirred at 60° for 5 h and then cooled. The solid was filtered off,washed successively with methanol (3×15 ml) and water (25 ml) and driedin vacuo to give the title compound (1.9 g), m.p. 223°-225°.

Intermediate 30(E)-1-(2-Methoxy-1-naphthalenyl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one

A mixture of 1-acetyl-2-methoxynaphthalene (1.14 g), Intermediate 1 (2.0g) and potassium hydroxide (0.5 g) in methanol (25 ml) was stirred at50° for 18 h, cooled and added to water (100 ml). The precipitate wascollected, recrystallised from hot methanol (ca. 50 ml) and dried togive the title compound (2.59 g), m.p. 220°-222°.

Intermediate 31(E)-3-(5-Methyl-1H-imidazol-4-yl)-1-(1H-pyrrolo-[2,3-b]-pyridin-3-yl-2-propen-1-one

A solution of 1-(1H-pyrrolo-[2,3-b]-pyridin-3-yl)ethanone (0.73 g) indry THF (40 ml) at -50° under nitrogen was treated with lithiumdiisopropylamide (1.5M solution in cyclohexane; 7.6 ml) and stirred at0° for 45 min. A solution of Intermediate 1 (2.4 g) in dry THF (20 ml)was added and the mixture was stirred for 5 min. It was then cooled to-50°, quenched with acetic acid (5 ml) and evaporated in vacuo. Aceticacid (90 ml) and p-toluenesulphonic acid monohydrate (5.0 g) were addedand the mixture was heated under nitrogen at reflux for 2.5 h. It wasthen cooled and partitioned between 2N sodium hydroxide (700 ml) anddichloromethane (4×250 ml); discarded). The aqueous phase was acidifiedto pH 7 (with 2N hydrochloric acid) and extracted withchloroform/methanol (3:2) (4×250 ml). These organic extracts were dried,evaporated in vacuo and the residual solid was triturated withdichloromethane/ether (1:1) (100 ml), to give the title compound (0.78g), t.l.c (System A, 89:10:1) Rf 0.1.

Intermediate 322,3-Dihydro-3(5-methyl-1H-imidazol-4-yl)-1H-naphtho[2,1-b]pyran-1-one

Lithium diisopropylamide (1.5M solution in cyclohexane; 7.9 ml) wasadded dropwise to a cold (-50°) stirred solution of1-(2-hydroxy-1-naphthalenyl)ethanone (1.0 g) in dry THF (75 ml) undernitrogen. After 45 min., Intermediate 1 (2.0 g) was added and stirringwas continued while warming to 0° over 1.25 h. Acetic acid (90 ml) wasadded to quench the reaction, followed by p-toluenesulphonic acidmonohydrate (5.0 g) and the solution was heated under nitrogen at refluxfor 24 h. The cooled solution was basified (to pH8) with 5N sodiumhydroxide and extracted with dichloromethane (4×150 ml). The combinedorganic layers were washed with brine (3×100 ml), dried and evaporatedin vacuo to give a solid. Trituration with methanol/water (9:1) (100 ml)followed by ether (3×50 ml) gave the title compound (930 mg), m.p.214°-217° (decomp.).

Intermediate 33 1 -(1-Methyl-1H-indole-4-yl)ethanone

Methyl lithium (1.59M solution in ether; 13.8 ml) was added dropwise toa stirred cold (-65° to -55°) solution of1-methyl-1H-indole-4-carboxylic acid (1.75 g) in dry THF (50 ml) undernitrogen and stirring was continued while the mixture warmed to 0° over2 h. The reaction was then quenched with saturated ammonium chloridesolution (50 ml) and the layers were separated. The aqueous layer wasfurther extracted with dichloromethane (2×50 ml) and the combinedorganic layers were washed with brine (2×50 ml), dried and evaporated invacuo. The residual solid (1.8 g) was purified by FCC eluting withdichloromethane to give the title compound (1.6 g), m.p. 63°-64°.

General Hydrogenation Procedure

Examples 1 to 15 were all prepared by hydrogenation of a solution orsuspension of the appropriate enone in methanol or ethanol at roomtemperature and atmospheric pressure over a stirred suspension ofpre-reduced 10% palladium oxide on carbon catalyst in methanol orethanol, until hydrogen uptake had ceased. The resulting suspension wasfiltered and the required product was obtained from the filtrate by oneof a variety of conventional purification techniques, and maleateformation. Maleate formation (except where otherwise stated) consistedof dissolving the free base in ethanol (either at room temperature or atan elevated temperature), and adding to this solution a solution ofmaleic acid in ethanol. The resulting solution was either evaporated todryness or diluted with dry ether to precipitate the title compound.Example 1 is described in full.

EXAMPLE 1 3-(5-Methyl-1H-imidazol-4-yl)-1-(2-naphthalenyl)-1-propanonemaleate

A solution of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-(2-naphthalenyl)-2-propen-1-onemaleate (300 mg) in hot methanol (90 ml) was hydrogenated at roomtemperature and atmospheric pressure over a stirred suspension ofpre-reduced 10% palladium oxide on carbon (50% aqueous paste; 30 mg) inmethanol (10 ml) for 16 h. The suspension was filtered, evaporated invacuo, and the residual oil (ca. 350 mg) was partitioned betweendichloromethane (3×50 ml) and 2N sodium carbonate (50 ml). The combinedorganic extracts were dried and evaporated in vacuo. The residual oil(300 mg) was dissolved in absolute ethanol (6 ml) and treated with asolution of maleic acid (100 mg) in ethanol (1 ml). Dilution with dryether (ca. 75 ml) afforded the title compound (210 mg) as a solid, m.p.137°-138∞, t.l.c. (System A, 89:10:1) Rf 0.33.

EXAMPLE 2 1-(5-Fluoro-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone maleate

The filtrate from the hydrogenation of1-(5-fluoro-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(1.01 g) was treated with maleic acid (418 mg) and the resultantsolution was evaporated to dryness to give a solid. This wasrecrystallised from methanol/ethyl acetate to give the title compound(920 mg), m.p. 138°-140°.

Analysis Found: C,63.5; H,4.6; N,6.9; C₁₇ H₁₅ FN₂).C₄ H₄ O₄ requiresC,63.3; H,4.8; N,7.0%.

EXAMPLE 3 3(5-Methyl-1H-imidazol-4-yl)-1-phenyl-1-propanone maleate

The filtrate from the hydrogenation of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-phenyl-2-propen-1-one maleate (0.37g) was concentrated in vacuo to ca. 5 ml and diluted with ether (200 ml)to precipitate a solid (290 mg). This was partitioned betweendichloromethane (2×50 ml) and 2N sodium carbonate solution (50 ml;discarded) and the combined organic layers were dried and evaporated invacuo. The resultant oil was purified by FCC eluting with System A(95:5:0.5) to give the free base of the title compound (132 mg) as asolid. Maleate formation gave the title compound (170 mg), m.p. 94°-95°.

Water Analysis Found: 0.8% w/w.tbd.0.15 mol H₂ O. Analysis Found:C,61.1;H,5.4;N,8.2; C₁₃ H₁₄ N₂₀.C₄ H₄ O₄.0.15 H₂ O requiresC,61.3;H,5.5;N,8.4%.

EXAMPLE 4 1-(2-Methoxyphenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)1-(2-methoxyphenyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(0.75 g) was evaporated to leave a semi-solid (ca. 0.75 g) which waspurified by SPCC eluting with System A (200:8:1) to give a gum (0.6 g).Maleate formation gave the title compound (0.69 g), m.p. 125°-128°.

Analysis Found: C,60.3; H,5.6; N,7.5; C₁₄ H₁₆ N₂ O₂.C₄ H₄ O₄ requiresC,60.0; H,5.6; N,7.8%.

EXAMPLE 53-(5-Methyl-1H-imidazol-4-yl)-1-(3,5-dimethylphenyl)-1-propanone maleate

The filtrate from the hydrogenation of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-(3,5-dimethylphenyl)-2-propen-1-one(0.2 g) was evaporated to give an oil (0.2 g) which was dissolved inmethanol (15 ml) containing maleic acid (0.1 g). The mixture wasevaporated to give a solid which was triturated with ether, filtered anddried in vacuo to give the title compound (0.21 g), m.p. 151°-152°.

Analysis Found: C,63.7; H,6.2; N,7.9; C₁₅ H₁₈ N₂ O.C₄ H₄ O₄ requiresC,63.7; H,6.2; N,7.8%.

EXAMPLE 61-(2-Methyl-3-benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone,compound with maleic acid

The filtrate from the hydrogenation of(E)-1-(2-methyl-3-benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(250 mg) was evaporated to give a solid (250 mg). The product of maleateformation was triturated with dry ether (3×30 ml) to give a solid (285mg), a sample of which (245 mg) was recrystallised from hotmethanol/ethyl acetate (1:3) to give the title compound (120 mg), m.p.213°-215°, t.l.c. on triethylamine impregnated silica (ethylacetate/methanol, 19:1) Rf 0.36.

N.m.r. indicates 0.32 mol of maleic acid present.

EXAMPLE 7 1-(2-Benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-1-(2-benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one (500mg) was evaporated and the resulting oil was purified by FCC elutingwith System A (100:10:1) to give the free base of the title compound(210 mg) as a foam. The product of maleate formation was recrystallisedfrom ethanol (8 ml) to give the title compound (160 mg), m.p. 152°-154°.

Analysis Found: C,61.3; H,4.9; N,7.4; C₁₅ H₁₄ N₂ O₂.C₄ H₄ O₄ requiresC,61.6; H,4.9; N,7.6%.

EXAMPLE 81-(2-Methylbenzo[b]thien-3-yl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-1-(2-methylbenzo[b]thien-3-yl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(195 mg) was evaporated to give an oil (160 mg). The product of maleateformation was triturated with dry ether (3×10 ml) to give the titlecompound (165 mg), m.p. 131°-132°.

Analysis Found: C,60.1; H,5.0; N,6.9; C₁₆ H₁₆ N₂ OS.C₄ H₄ O₄ requiresC,60.0; H,5.0; N,7.0%.

EXAMPLE 91-(Benzo[b]thien-2-yl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone,compound with maleic acid

The filtrate from the hydrogenation of(E)-1-(benzo[b]thien-2-yl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(667 mg) was treated with maleic acid (145 mg). The resultant solutionwas evaporated to give a solid which was heated to reflux in ethylacetate (150 ml) and the suspension was then cooled to room temperature.The organic solution was decanted and the remaining solid was dried invacuo to give the title compound (371 mg), m.p. 141°-143°. N.m.r.indicates 0.8 mol of maleic acid present.

Water Analysis Found: 1.5% w/w.tbd.0.27 mol H₂ O. Analysis Found:C,59.0; H,4.8; N,7.2; C₁₅ H₁₄ N₂ OS.O.8C₄ H₄ O₄ 0.27 H₂ O requiresC,59.4; H,4.9; N,7.6%.

EXAMPLE 10 1-(3-Benzofuranyl)-3(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-1-(3-benzofuranyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one (200mg) was evaporated to give an oil (169 mg). The solid product of maleateformation was recrystallised from ethanol (4 ml) to give the titlecompound (118 mg), m.p. 139°-140°.

Analysis Found: C,61.6; H,4.9; N,7.6; C₁₅ H₁₄ N₂ O₂.C₄ H₄ requiresC,61.6; H,4.9; N,7.6%.

EXAMPLE 113-(5-Methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-2-yl)-propanonemaleate

The filtrate from the hydrogenation of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-2-yl)-2-propen-1-one(295 mg) was evaporated to give a solid (250 mg). Maleate formation gavea solid (194 mg), a portion of which (180 mg) was treated with 8%aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate. Theorganic extract was dried and evaporated to give an oil which waspurified by FCC eluting with System A (100:10:1) to give the free baseof the title compound as an oil. Maleate formation gave the titlecompound (160 mg), m.p. 137°-139°.

Analysis Found: C,62.4; H,5.5; N,10.8; C₁₆ H₁₇ N₃ O.C₄ H₄ O₄ requiresC,62.7; H,5.5; N,11.0%.

EXAMPLE 123-(5-Methyl-1H-imidazol-4-yl)-1)1H-pyrrolo-[2,3-b]-pyridin-3-yl)-1-propanonemaleate

A solution of(E)-3-(5-methyl-1H-imidazol-4-yl)-1)1H-pyrrolo-[2,3-b]-pyridin-3-yl)-2-propen-1-one(300 mg) in dichloromethane/methanol (1:1) (100 ml) was hydrogenated asdescribed in the General Procedure. The resulting filtrate wasevaporated in vacuo to give a foam (0.3 g). Maleate formation gave asolid (235 mg), a portion of which (210 mg) was partitioned betweenchloroform/methanol (5:1) (3×50 ml) and 2N sodium carbonate (50 ml) andthe combined, dried organic layers were evaporated in vacuo to give asolid (155 mg). Maleate formation gave the title compound (210 mg), m.p.185°-190°.

Analysis Found: C,58.4; H,5.0; N,15.0; C₁₄ H₁₄ N₄ O.C₄ H₄ O₄ requiresC,58.4; H,5.0; N,15.1%.

EXAMPLE 133-(5-Methyl-1H-imidazol-4-yl)-1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-2-propen-1-one(520 mg) was evaporated to give the free base of the title compound asan oil (480 mg). The product of maleate formation was crystallised fromethyl acetate (80 ml) to give the title compound (516 mg), m.p.106°-108°.

Water Analysis Found: 1.87% w/w.tbd.0.38 mol H₂ O. Analysis Found:C,58.6; H,6.3; N,11.2; C₁₄ H₁₉ N₃ O.C₄ H₄ O₄.0.38 H₂ O requires C,58.7;H,6.5; N,11.4%.

EXAMPLE 141-(2,5-Dimethyl-3-furanayl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-1-(2,5-dimethyl-3-furanyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one(485 mg) was evaporated to give the free base of the title compounds asan oil (460 mg). The product of maleate formation was crystallised fromethanol (15 ml) to give the title compound (303 mg), 130°-131°.

Analysis Found: C,59.0; H,5.9; N,8.0; C₁₃ H₁₆ N₂ O₂.C₄ H₄ O₄ requiresC,58.6; H,5.8; N,8.0%.

EXAMPLE 151-(2,5-Dimethyl-3-thienyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

The filtrate from the hydrogenation of(E)-1-(2,5-dimethyl-3-thienyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-onehemi-succinate (200 mg) was evaporated to give a gum (0.25 g) which wasadsorbed onto silica (ca. 1 g) and purified by FCC eluting with System A(75:8:1) to give the free base of the title compound (0.15 g). Maleateformation gave the title compound (0.175 g), m.p. 126°-128°.

Analysis Found: C,56.2; H,5.6; N,7.5; C₁₃ H₁₆ N₂ OS.C₄ H₄ O₄ requiresC,56.0; H,5.5; N,7.7%.

EXAMPLE 16 3-(5-Methyl-1H-imidazol-4-yl)-1-(1-naphthalenyl)-1-propanonesuccinate

A suspension of(E)-3-(5-methyl-1H-imidazol-4-yl)-1-(1-naphthalenyl)-2-propen-1-onemaleate (0.38 g) in methanol (50 ml) was hydrogenated at roomtemperature and atmospheric pressure over a stirred suspension ofpre-reduced 10% palladium oxide on carbon (50% aqueous paste; 40 mg) inmethanol (10 ml) for 2 h. The reaction mixture was filtered, thefiltrate was concentrated in vacuo to ca. 5 ml, and diluted with dryether (ca. 150 ml) to precipitate the title compound (0.28 g) as asolid, m.p. 107°-108°.

Analysis Found: C,65.9; H,5.8; N,7.1; C₁₇ H₁₆ N₂ O.C₄ H₆ O₄ requiresC,66.0; H,5.8; N,7.3%.

EXAMPLE 171-(4-Methoxy-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

A solution of(E)-1-(4-methoxy-1-naphthalenyl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one(0.9 g) in a mixture of THF (15 ml), water (3 ml) and acetic acid (2 ml)was heated on a steam bath for 30 min. The mixture was then concentratedto remove most of the THF and the residue was diluted with 0.5Mhydrochloric acid (10 ml). The mixture was washed with ether (2×25 ml;discarded, basified with solid potassium carbonate and extracted withdichloromethane (2×25 ml). The organic phase was dried and evaporated togive a solid (0.4 g) which was dissolved in ethanol (25 ml) andhydrogenated at room temperature and atmospheric pressure over a stirredsuspension of pre-reduced 10% palladium oxide on carbon (50% aqueouspaste; 0.1 g) in ethanol for 1 h. The mixture was filtered and maleicacid (0.15 g) was dissolved in the filtrate. The filtrate was thenevaporated in vacuo to give a solid which was triturated with ether (50ml) and filtered to give the title compound (0.35 g), m.p. 150°-151°.

Analysis Found: C,64.25; H,5.5; N,6.7; C₁₈ H₁₈ N₂ O₂.C₄ H₄ O₄ requiresC,64.4; H,5.4; N,6.8%.

EXAMPLE 183-(5-Methyl-1H-imidazol-4-yl)-1-(2-methyl-1-naphthalenyl)-1-propanonemaleate

A mixture of(E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(2-methyl-1-naphthalenyl)-2-propen-1-one(1.25 g), acetic acid (10 ml), THF (10 ml) and water (10 ml) was heatedon a steam bath for 1 h. The mixture was then hydrogenated according tothe General Procedure and the resulting filtrate was evaporated in vacuoand partitioned between dichloromethane (3×75 ml) and 0.2N sodiumhydroxide (100 ml). The combined organic layers were dried andevaporated in vacuo to leave a foam (1.3 g) which was purified by FCCeluting with System A (94.5:5:0.5) to give the free base of the tilecompound as an oil. The product of maleic acid formation was trituratedwith ether to give the title compound (0.78 g), m.p. 108°-109°.

Analysis Found: C,66.7; H,5.5; N,6.9; C₁₈ H₁₈ N₂ O.C₄ H₄ O₄ requiresC,67.0; H,5.6; N,7.1%.

EXAMPLE 191-[(1,1'-Biphenyl)-3-yl]-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

A solution of(E)-1-[(1,1'-biphenyl)-3-yl]-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one(0.7 g) in a mixture of THF (15 ml), water (5 ml), and acetic acid (3ml) was heated on a steam bath for 1 h. The mixture was basified with 2Nsodium carbonate and extracted with dichloromethane (2×30 ml). Thecombined, dried organic extracts were evaporated to give an oil whichwas purified by FCC eluting with ethyl acetate/triethylamine (100:1) andthen with ethyl acetate/methanol (5:1) to give a foam (0.26 g) which washydrogenated according to the General Procedure. Maleic acid (0.1 g) wasdissolved in the resulting filtrate and the solution was evaporated togive a gum which was triturated with ether to give the title compound(0.26 g) as a solid, m.p. 122°-123°.

Analysis Found: C,68.2; H,5.6; N,7.0; C₁₉ H₁₈ N₂ O.C₄ H₄ O₄ requiresC,68.0; H,5.5; N,6.9%.

EXAMPLE 203-(5-Methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indazol-3-yl)-1-propanonemaleate

A mixture of(E)-1-(1-methyl-1H-indazol-3-yl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one(1.3 g) in water (10 ml), acetic acid (10 ml) and THF (10 ml) was heatedat reflux for 1 h, and then cooled. It was then mixed with ethanol (70ml) and hydrogenated at room temperature and atmospheric pressure over astirred suspension of pre-reduced 10% palladium oxide on carbon (130 mg)in ethanol for 1 h. The mixture was filtered, evaporated in vacuo andthe residual semi-solid was purified by FCC eluting with System A(89:10:1) to give the free base of the title compound as a solid (0.62g). This was dissolved in ethanol (15 ml) and treated with a solution ofmaleic acid (275 mg) in methanol (1 ml). Concentration in vacuo to 2 mlfollowed by dilution with ethyl acetate (50 ml) afforded the titlecompound (0.75 g), m.p. 153°-154°.

Analysis Found: C,59.4; H,5.3; N,14.3; C₁₅ H₁₆ N₄ O.C₄ H₄ O₄ requiresC,59.4; H,5.2; N,14.6%.

EXAMPLE 211-(2-Methoxy-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone,compound with hydrogen chloride and acetic acid

(E)-1-(2-Methoxy-1-naphthalenyl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propen-1-one(1.0 g) was hydrogenated according to the General Procedure and theresulting filtrate was evaporated in vacuo. A mixture of water (10 ml),acetic acid (10 ml) and THF (10 ml) was added and the mixture was heatedon a steam bath for 1.5 h. The solution was cooled and partitionedbetween 0.2N hydrochloric acid (150 ml) and dichloromethane (150 ml;discarded). The aqueous phase was basified with 2N sodium hydroxide (topH7) and extracted with dichloromethane (3×150 ml). The combined, driedorganic layers were evaporated in vacuo and the residual oil wastriturated with dry ether (75 ml) to give the title compound (0.47 g) asa solid, m.p. 153°-158°, t.l.c. (System A, 89:10:1) Rf 0.44.

N.m.r. indicates 0.33 mol acetic acid present. Analysis Found:C,66.2;H,6.1;N,8.1;Cl,6.8; C₁₈ H₁₈ N₂ O₂.O.33C₂ H₄ O₂.O.66HCl requiresC,66.2;H,5.95;N,8.3;Cl,6.9%.

EXAMPLE 22 3-(5-Methyl-1H-imidazol-4-yl)-1-(4-quinolinyl)-1-propanonemaleate

A solution of 3-(5-methyl-1H-imidazol-4-yl)-1-(quinolin-4-yl)-2-propen-1-one (0.4 g) andtris(triphenylphosphine)rhodium (I) chloride (0.08 g) in toluene (90 ml)and ethanol (60 ml) was stirred under hydrogen for 4 h. A further batchof tris(triphenylphosphine)rhodium (I) chloride (0.02 g) was added andthe solution was stirred under hydrogen at 20° for 1 h and then at 50°for 1 h. The solution was then evaporated in vacuo to give a gum (ca.0.6 g) which was purified by FCC eluting with System A (89:10:1) to givea gum (0.083 g) which was dissolved in absolute ethanol (1 ml) andtreated with a solution of maleic acid (36 mg) in ethanol (1 ml). Theresulting solution was diluted with ether (ca. 50 ml) to precipitate thetitle compound (87 mg) as a solid, m.p. 110°-112°, t.l.c. (System A,89:10:1) Rf 0.25.

EXAMPLE 231-(2-Hydroxy-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

A suspension of2,3-dihydro-3-(5-methyl-1H-imidazol-4-yl)-1H-naphtho[2,1-b]pyran-1-one(400 mg) in ethanol (60 ml) was added to a stirred suspension of 10%palladium on carbon (45 mg) in ethanol (15 ml) under hydrogen. After 2h, a solution of potassium hydroxide (100 mg) in methanol (2.5 ml) wasadded. Stirring was continued for 5 h and the reaction was thenneutralised with saturated ammonium chloride solution (5 ml), filteredand evaporated in vacuo. The residual oil was dissolved in ethanol (5ml) and treated with a solution of maleic acid (167 mg) in ethanol (2ml). Dilution with ether (100 ml) afforded a gum which, on triturationwith hot ethyl acetate, gave a solid which was recrystalised fromethanol/ethyl acetate (1:5) (70 ml) to give a solid (0.3 g). The motherliquors were evaporated in vacuo, combined with this solid, andpartitioned between dichloromethane (3×50 ml) and 2N sodium carbonatesolution (50 ml). The combined, dried organic layers were evaporated andpurified by FCC eluting with System A (95:5:0.5), to give the free baseof the title compound as a foam (315 mg). This was dissolved in ethanol(5 ml), treated with a solution of maleic acid (125 mg) in ethanol (1ml) and diluted with dry ether (75 ml) to give the title compound (315mg) as a solid, m.p. 155°-157°.

Analysis Found: C,63.4; H,5.0; N,6.9; C₁₇ H₁₆ N₂ O₂.C₄ H₄ O₄ requiresC,63.6; H,5.1; N,7.1%.

EXAMPLE 241-(Benzo[b]thien-3-yl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone maleate

A solution of potassium hydroxide (1.0 g) in methanol (10 ml) was addedto a solution of 3-acetylbenzol[b]thiophene (2.0 g) and Intermediate 1(4.0 g) in methanol (40 ml) under nitrogen. The mixture was stirred atreflux for 4 h then at room temperature for 65 h. The suspension wasfiltered and the solid obtained was heated at reflux in a mixture ofacetic acid (20 ml), water (20 ml) and THF (20 ml) for 1.5 h. Thesolution was allowed to cool to room temperature and was thenhydrogenated at room temperature and atmospheric pressure over a stirredsuspension of pre-reduced 10% palladium oxide on carbon (50% aqueouspaste, 2.0 g) in ethanol (50 ml) for 18 h. The mixture was filtered,evaporated and the residue was treated with saturated potassiumcarbonate solution (100 ml) and extracted with dichloromethane (3×50ml). The combined organic extracts were dried and evaporated to give anoil (ca. 5.5 g) which was purified by FCC eluting with System A(150:10:1 ) to give a foam (1.52 g). This material was dissolved indichloromethane (20 ml) and treated with a solution of maleic acid (686mg) in ethanol (5 ml). The solvent was removed in vacuo and the residuewas triturated with dry ether (5×30 ml) to give the title compound as asolid (1.87 g),m.p. 164°-165°. The sample was dried in vacuo at 100° for24 h and was then dissolved in hot ethanol (100 ml). The resultantsolution was filtered and the filtrate was evaporated to leave a solid.Dry ether (150 ml) was added and the suspension was filtered. The solidobtained was washed with dry ether (3×50 ml) and dried in vacuo at 75°for 36 h to give the title compound (1.77 g) as a solid, m.p. 164°-165°.

N.m.r. indicates 0.55% w/w ethanol present≡0.046 mol. Water AnalysisFound 0.87% w/w≡0.19 mol H₂ O. Analysis Found: C,58.9;H,4.7;N,7.1; C₁₅H₁₄ N₂ OS.C₄ H₄ O₄.O.19H₂ 0.0.046C₂ H₅ OH requires C,58.5;H,4.8;N,7.2%.

EXAMPLE 251-(6-Fluoro-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanonemaleate

A suspension of 1-(6-fluoro-1-naphthalenyl)ethanone (404 mg) andIntermediate 1 (760 mg) in methanol (10 ml) was treated with a solutionof potassium hydroxide (180 mg) in methanol (2 ml). The mixture washeated at reflux for 4 h, allowed to stand at room temperature for 18 hand then concentrated in vacuo to ca. 2 ml. Acetic acid (8 ml), water (5ml) and THF (15 ml) were added and the solution was heated at reflux for3 h. The reaction mixture was added cautiously to 8% aqueous sodiumbicarbonate (150 ml) and the mixture was extracted with dichloromethane(3×40 ml). The combined, dried organic extracts were evaporated to givean oil which was hydrogenated according to the General Procedure and theresulting filtrate was evaporated to give an oil. This oil was purifiedby FCC eluting with System A (100:3:0.3) and then with System A(100:10:1) to give a solid (374 mg) which was dissolved in ethanol (20ml) and treated with a solution of maleic acid (154 mg) in ethanol (20ml). The mixture was evaporated to give a solid which was stirred underdry ether (100 ml) for 1 h to give a fine suspension. The ether wasdecanted and the remaining solid was dried in vacuo to give the titlecompound (487 mg), m.p. 145-148°.

Analysis Found: C,63.3; H,4.8; N,6.9; C₁₇ H₁₅ N₂ O.C₄ H₄ O₄ requiresC,63.3; H,4.8; N,7.0%.

EXAMPLE 263-(5-Methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-4-yl)-1-propanonemaleate

A mixture of 1-(1-methyl-1H-indol-4-yl)ethanone (0.75 g), Intermediate 1(1.5 g) and potassium hydroxide (0.375 g) in methanol (12.5 ml) wasstirred at 50° for 24 h. The cooled mixture was partitioned betweendichloromethane (3×75 ml) and brine (75 ml) and the combined, driedorganic extracts were evaporated in vacuo. The residual foam (2.3 g) washeated at reflux in a mixture of water (10 ml), acetic acid (10 ml) for2 h. The cooled solution was hydrogenated at room temperature andatmospheric pressure over a stirred suspension of pre-reduced 10%palladium oxide on carbon (50% aqueous paste; 200 mg) in ethanol for 1h. The suspension was filtered, evaporated in vacuo, and the residue (7g) was purified by FCC eluting with System A (89:10:1) to give the freebase of the title compound as a foam (1.03 g). This was dissolved inethanol (10 ml) and treated with a solution of maleic acid (447 mg) inmethanol (1 ml). Dilution with dry ether (100 ml) afforded the titlecompound (1.18 g), m.p. 130°-131°.

Analysis Found: C,62.3; H,5.5; N,10.8; C₁₆ H₁₇ N₃ O.C₄ H₄ O₄ requiresC,62.65; H,5.5; N,11.0%.

The following examples illustrate pharmaceutical formulations accordingto the invention. The term "active ingredient" is used herein torepresent a compound of formula (I).

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as hydroxypropyl methylcellulose, using standard techniques.Alternatively the tablets may be sugar coated.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to excipients or the compression weight and usingpunches to suit.

    ______________________________________                                        CAPSULES                                                                                      mg/capsule                                                    ______________________________________                                        Active Ingredient 0.5                                                         *Starch 1500      98.5                                                        Magnesium Stearate BP                                                                           1.0                                                         Fill Weight       100.0                                                       ______________________________________                                         *a form of directly compressible starch.                                 

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight andif necessary changing the capsule size to suit.

    ______________________________________                                        Direct Compression Tablet                                                                          mg/tablet                                                ______________________________________                                        Active Ingredient       0.50  10.00                                           Calcium Hydrogen Phosphate BP*                                                                       87.25  77.75                                           Croscarmellose Sodium NF                                                                              1.80   1.80                                           Magnesium Stearate BP   0.45   0.45                                           Compression weight     90.00  90.00                                           ______________________________________                                         *of a grade suitable for direct compression.                             

The active ingredient is passed through a 60 mesh sieve, blended withthe calcium hydrogen phosphate, croscarmellose sodium and magnesiumstearate. The resultant mix is compressed into tablets using a ManestyF3 tablet machine fitted with 5.5 mm, flat bevelled edge punches.

SYRUP

This may be either a sucrose or sucrose free presentation.

    ______________________________________                                        Sucrose-Free Syrup       mg/5 ml dose                                         ______________________________________                                        Active Ingredient            0.5                                              Hydroxypropylmethylcellulose USP                                                                           22.5                                             (viscosity type 4000)                                                         Buffer                                                                        Flavour                                                                       Colour                       as required                                      Preservative                                                                  Sweetener                                                                     Purified Water BP to         5.0 ml                                           ______________________________________                                    

The hydroxypropylmethylcellulose is dispersed in hot water, cooled andthen mixed with an aqueous solution containing the active ingredientsand the other components of the formulation. The resultant solution isadjusted to volume and mixed. The syrup is clarified by filtration.

    ______________________________________                                        INJECTION FOR INTRAVENOUS ADMINISTRATION                                                      mg/ml                                                         ______________________________________                                        Active ingredient 0.05      1.0                                               Sodium Chloride BP                                                                              as required                                                                             as required                                       Water for Injection BP to                                                                       1.0 ml    1.0 ml                                            ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or facilitate solution of the active ingredient.Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively, the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

I claim:
 1. A compound of formula (I): ##STR11## or a physiologicallyacceptable salt or solvate thereof, wherein R¹ and R², which may be thesame or different, each represents a hydrogen atom or a C₁₋₆ alkylgroup;Im represents an imidazolyl group of formula: ##STR12## whereinone of the groups represented by R³,R⁴ and R⁵ is a hydrogen atom or aC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl or phenylC₁₋₃ alkylgroup, and each of the other two groups, which may be the same ordifferent, represents a hydrogen atom or a C₁₋₆ alkyl group; and A is agroup of formula (c) or (e): ##STR13## wherein R¹³ represents a hydrogenatom, a halogen atom, or a hydroxy, C₁₋₄ alkoxy or C₁₋₄ alkyl group, ora group --NR⁸ R⁹ (wherein R⁸ and R⁹, which may be the same or different,each represents a hydrogen atom or a C₁₋₄ alkyl group, or together withthe nitrogen atom to which they are attached form a saturated 5 to 7membered ring); R¹⁴ represents a hydrogen atom, a halogen atom, or aC₁₋₄ alkyl or phenyl group; D represents an oxygen atom or a sulphuratom; R¹⁵ represents a hydrogen atom, or a C₁₋₄ alkyl or phenyl group;R¹⁶ represents a hydrogen atom, a halogen atom, or a C₁₋₄ alkyl group;with the provisos that when the group --COCR¹ R² CH₂ Im is attached atthe 3-position of the group (e), R¹⁴ represents a hydrogen atom, ahalogen atom or a C₁₋₄ alkyl group, and R¹⁶ represents a hydrogen atomor a C₁₋₄ alkyl group; and E represents an oxygen atom or a sulphuratom, or a group NR¹⁷ wherein R¹⁷ represents a hydrogen atom or a C₁₋₆alkyl group.
 2. A compound according to claim 1 in which R¹ and R² eachrepresent a hydrogen atom.
 3. A compound according to claim 1 in whichR³, R⁴ and R⁵ each independently represent a hydrogen atom or a C₁₋₄alkyl group.
 4. A compound according to claim 1 in which R³ and R⁴ eachrepresent a hydrogen atom and R⁵ is a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆alkenyl, phenyl or phenylC₁₋₃ alkyl group.
 5. A compound according toclaim 1 in which A is a group (c) and R¹³ represents a hydrogen atom,and R¹⁴ represents a hydrogen atom or a C₁₋₄ alkyl group.
 6. A compoundaccording to claim 1 in which A is a group (e), and two of R¹⁴, R¹⁵ andR¹⁶ represent a C₁₋₄ alkyl group, and the other represents a hydrogenatom, and the group --COCR¹ R² CH₂ Im is attached at the 3-position ofthe heterocycle, and when E represents the group NR¹⁷, R¹⁷ is a C₁₋₄alkyl group.
 7. A compound according to claim 1 in which the group A isa group represented by the formula (c) wherein the group --COCR¹ R² CH₂Im is attached at the 3-position of the benzofuran or benzothiophenemoiety. 8.1-(Benzo[b]thien-3-yl)-3-(5-methyl-1H-imidazol-4-yl)-1-propanone, or aphysiologically acceptable salt or solvate thereof.
 9. A pharmaceuticalcomposition which comprises an effective amount of a compound of formula(I) as defined in claim 1 or a physiologically acceptable salt orsolvate thereof together with at least one physiologically acceptablecarrier or diluent.
 10. A method of treating a condition caused bydisturbance of "neuronal" 5HT function which comprises administering toa patient an effective amount of a compound of formula (I) as defined inclaim 1 or a physiologically acceptable salt or solvate thereof torelieve said condition.